© 2005 European Society of Cardiology
Work-rate affects cardiopulmonary exercise test results in heart failure
a Centro Cardiologico Monzino IRCCS, Institute of Cardiology, University of Milan 20138 Milan, Italy
b Fondazione Salvatore Maugeri IRCCS, Divisione di Cardiologia, Centro Medico di Cassano Murge Bari, Italy
c Division of Respiratory and Critical Care Medicine, Department of Medicine, Harbor-University of California Los Angeles Medical Center, University of California Los Angeles School of Medicine Torrance, CA 90509, USA
* Corresponding author. Tel.: +39 2 58002299; Fax: +39 2 58011039. E-mail address: Piergiuseppe.Agostoni{at}ccfm.it
 |
Abstract |
|---|
 Top Abstract 1. Methods2. Results3. DiscussionAcknowledgmentsReferences |
|---|
Aims: Cardiopulmonary exercise test (CPET) is used to evaluate patients with chronic heart failure (HF) usually by means of a personalized ramp exercise protocol. Our aim was to evaluate if exercise duration or ramp rate influences the results.
Methods and results: Ninety HF patients were studied (peak VO2: >20 ml/min/kg, n=28, 15>20 ml/min/kg, n=39 and <15 ml/min/kg, n=23). Each patient did four CPET studies. The initial study was used to separate the subjects into three groups, according to their exercise capacity. In the remaining studies, work-rate was increased at three different rates designed to have the subjects reach peak exercise in 5, 10 and 15 min from the start of the ramp increase in work-rate, respectively. The order was randomized. The work-rate applied for the total population averaged 22.7±8.0, 11.6±3.7, 7.5±2.9 W/min with effective loaded exercise duration of 5 min and 16 s±29 s, 9 min and 43 s±49 s and 14 min and 32 s±1 min and 12 s for the 5-, 10- and 15-min tests, respectively. Peak VO2 averaged 16.9±4.3*, 18.0±4.4 and 18.0±5.4 ml/min/kg for the 5-, 10- and 15-min tests, (*=p<0.001 vs. 10 min). The shortest test had the lowest peak heart rate and ventilation and highest peak work-rate. Peak VO2 and heart rate were lowest in 5-min tests regardless of HF severity. The 
VO2/work-rate was lowest in 5-min tests and highest in 15-min tests. At all ramp rates, VO2/work-rate was lower for the subjects with the lower peak VO2. The VE/VCO2 slope and VO2 at anaerobic threshold were not affected by the protocol for any grade of HF.
Conclusions: In chronic HF, exercise protocol has a small effect on peak VO2 and VO2/work but does not affect VO2 at anaerobic threshold and VE/VCO2 slope.
Key Words: Exercise • Oxygen consumption • Heart failure
Received December 17, 2003; Revised April 30, 2004; Accepted June 10, 2004
In chronic heart failure (HF), a cardiopulmonary exercise test (CPET) is frequently done to evaluate the severity of the disease, and thereby the patient's prognosis, or to test the efficacy of therapy [1–8]. For these purposes, several CPET parameters have been studied including oxygen uptake (
O2) at peak exercise and at anaerobic threshold, work-rate achieved at peak exercise, slope of ventilation (E) vs. carbon dioxide output (CO2), E/CO2 ratio at anaerobic threshold, 
O2/work-rate from unloaded cycling to peak, and the oxygen pulse (O2p) at peak O2 [9]. Some of these parameters are independent of each other and have specific prognostic relevance; as a consequence their combined use improves our capability to evaluate prognosis in HF patients [9,10]. While it is generally recommended to use a personalized exercise protocol in which work-rate is increased in ramp pattern aimed at achieving target time to peak exercise within 8–12 min [9,11–13], the exercise protocol is rarely provided in clinical study reports. Because it is not known if and how the duration, or the rate of increase of exercise load, affects the results obtained by CPET in the general HF population, and in subgroups of patients divided by HF severity, we investigated the effect of rate of work-rate increase, selected to reach the subject's peak exercise tolerance in approximately 5, 10 and 15 min, on the major exercise parameters of aerobic function and ventilatory efficiency. |
1. Methods |
|---|
|
TopAbstract1. Methods2. Results3. DiscussionAcknowledgmentsReferences |
|---|
1.1. Patient population
We studied 90 patients, 70 male and 20 female (age 59.3±0.7 years), with chronic HF in stable clinical condition and stable drug treatment for at least 2 months. These patients were followed regularly at single specialized Heart Failure Unit. Mean left ventricular ejection fraction, evaluated by echocardiography, was 36.2±10.9%. Cause of heart failure was idiopathic cardiomyopathy in 43 cases, ischemic cardiomyopathy in 44 and valvular heart disease in 3. All patients were on an optimized drug regimen, which included diuretics (72 cases), ACE-inhibitors (75 cases), angiotensin 1 receptor (AT1)-blockers (16 cases), beta-adrenergic receptor blockers (43 cases), anti-aldosteronic drugs (41 cases), digitalis (25 cases), and amiodarone (29 cases). Forty-seven and 43 patients were in New York Heart Association class II and III, respectively. According to the Weber classification [1], which is based on peak
O2, 28 patients were in class A (peak O2>20 ml/min/kg, age 57.1±0.7 years), 39 in class B (peak O2 between 15 and 20 ml/min/kg, age 59.7±1.4) and 23 in class C (peak O2<15 ml/min/kg, age 61.1±4.9). Patients were studied between June 1998 and May 2002. All patients were evaluated by the same medical staff using the same instruments (V-Max, Ergo 800 S and 12-lead ECG recorder Max-1; Sensor Medics, Yorba Linda, CA). The study was approved by the Institutional Ethics Committee and each subject provided written informed consent to the study.
1.2. Study protocol
All subjects had previous experience with cycle ergometer CPETs in our laboratory [14]. The protocol consisted of four-cycle ergometer CPETs performed with a ramp protocol, with breath-by-breath analysis of expiratory O2 and CO2 concentrations and ventilation and 12-lead EKG recording. The first test was utilized to assess the patients exercise capacity. The work-rate of the ramp protocol of this first test was decided on the basis of each patient clinical evaluation and on previous tests. The work-rate reached by the patient in the first test was utilized to target the ramp work-rate for the other three remaining tests, with the aim of achieving peak exercise in 5, 10 and 15 min, respectively. The order of these three tests was randomized. In each test, the loaded cycling period was preceded by 3 min of unloaded cycling. Tests were performed at about 60 rpm. All four tests were done within 10 working days with a minimum test-to-test interval of 48 h. The patients determined when they reached their peak exercise tolerance; however, they were strongly encouraged to perform a maximal effort. Neither patients nor laboratory personnel knew the protocol in use or the time course of the test, both being concealed from the monitor.
1.3. Data analysis
Data were collected breath-by-breath but specific time-related values are reported as means over 20 s. Peak exercise was considered the highest O2 achieved during active exercise or early recovery. Anaerobic threshold was measured with the V-slope analysis of CO2 vs. O2. The anaerobic threshold value was confirmed by ventilatory equivalents (increase of E/O2 with a constant E/CO2) and end-tidal pressure (increase of end-tidal PO2 with constant end-tidal PCO2). Oxygen pulse was calculated as O2/heart rate at peak exercise. The slope of the O2/work-rate relationship was calculated by computerized linear regression analysis from O2 increase from the end of unloaded cycling to peak exercise [15]. The E/CO2 slope was calculated as the slope of the linear relationship between E and CO2 from the beginning of loaded exercise and the end of the isocapnic buffering period identified where end-tidal PCO2 starts to decrease. Periodic breathing was defined as exercise-induced oscillatory changes in O2 and CO2 during exercise with a period of approximately 1 min. Two experts independently read each test.
1.4. Statistical Analysis
The data are reported as mean±S.D. Comparisons were made by one-way ANOVA followed by paired t-test as appropriated. The 10-min test was used as the reference work-rate protocol for the 5- and 15-min tests to which they were compared.
|
2. Results |
|---|
|
TopAbstract1. Methods2. Results3. DiscussionAcknowledgmentsReferences |
|---|
All patients completed the trial. In three cases, some tests were postponed for a few days because of interceding reasons. The respiratory exchange ratio (
CO2/O2) at peak exercise was >1.0 in all subjects suggesting that, at least, a near maximal exercise was performed; the respiratory exchange ratio achieved was not significantly different among the three tests (1.05±0.2, 1.09±0.2 and 1.06±0.2, for the 5-, 10- and 15-min test durations, respectively). The average work-rate applied was 22.7±8.0, 11.6±3.7 and 7.5±2.9 W/min for the 5-, 10- and 15-min tests, respectively. Periodic breathing was observed in 13 patients (1 in class A, 4 in class B and 8 in class C) and, if present, was observed in all the tests regardless of the exercise protocol. Exercise-induced periodic breathing disappeared during the test usually around anaerobic threshold. The effective loaded exercise duration was 5 min and 16 s±29 s, 9 min and 43 s±49 s and 14 min and 32 s±1 min and 12 s for the 5-, 10- and 15-min tests. Peak exercise measurements, O2/work-rate and E/CO2, for the entire study population are reported in Table 1. Peak O2, CO2 and heart rate were lower in the 5-min test compared to both longer tests. In the 5-min test, E was the lowest due to a low respiratory rate and end-tidal PCO2 was the highest. The E/CO2 slope and O2 at anaerobic threshold were not affected by the exercise protocol (Table 1).
|
Regardless of the exercise protocol used, the heart rate at peak exercise was lower in class B and C patients compared to class A patients (p<0.01 for class A vs. class B and class C) (Table 2). Heart rate and
O2 at peak exercise were lowest in the 5-min test in all classes of patients (Table 2). In contrast, the work-rate achieved was lowest at peak exercise in the 15-min test for all three heart failure classes (Table 2). The O2/work-rate was lowest in class C patients regardless of rate of increase in work-rate or exercise duration (Fig. 1). The O2/work-rate had a progressively lower slope from the 15-min test to the 5-min test for all three heart failure classes (Fig. 2). At the 10-min test, peak O2 pulse was 12.6±3.0*
, 10.0±2.9 and 7.3±1.4* ml/min/beat in class A, class B and class C, respectively (*p<0.001 vs. class B patients, p<0.001 vs. class C patients). The peak O2 pulse value was not affected by the ramp protocol applied (Tables 1 and 2).
|
|
|
At peak exercise,
E was: in class C highest with the 10-min protocol; in class B lowest for the 5-min protocol; and in class A lowest for the 5-min and highest for the 15-min protocols, respectively (Table 3). E differences among the exercise protocols were mainly due to respiratory rate changes (Table 3). As the functional class worsened, the slope of E/CO2 was progressively higher; however, the exercise protocol did not influence the E/CO2 slope (Table 3).
|
Anaerobic threshold was not clearly identified in five patients and, therefore, anaerobic threshold data refer to 85 of the 90 subjects (Table 4). The all-group average anaerobic thresholds were at 74±32*, 64±30 and 58±28
W with the 5-, 10- and 15-min tests, respectively (*p<0.001, p<0.01), with it being progressively reduced as the functional class worsened. However, O2 at the anaerobic threshold, E/CO2 and E/O2 at anaerobic threshold were unaffected by the ramp protocol, in all groups of patients (Table 4).
|
|
3. Discussion |
|---|
|
TopAbstract1. Methods2. Results3. DiscussionAcknowledgmentsReferences |
|---|
This study shows that, for any grade of HF, among the most relevant CPET measurements,
O2 at anaerobic threshold and E/CO2 slope are independent of the work-rate applied and test duration. Peak O2 was mildly reduced for the test in which work-rate was increased most rapidly. The shortest duration test was accompanied by the lowest peak exercise heart rate and ventilation (Table 1). Importantly, we showed that the O2/work-rate, which depends on the ability of the circulatory delivery of O2 to keep pace with the O2 requirement, was reduced as rate of work-rate increased and as heart failure worsened (Table 1; Figs. 1 and 2). The exercise tests were done with different ramp protocols to achieve peak exercise in 5, 10 and 15 min. All of the possible problems related to patient familiarization with laboratory and staff [14] was avoided by studying patients who were regularly followed in a single Heart Failure Unit. All patients performed CPETs in the same laboratory including a formal familiarization test, and were repeatedly evaluated with the same instruments and by the same personnel. We used the 10-min test as reference for short, 5-min, and long, 15-min, tests. The 10-min test was chosen because 10 min is the duration considered optimal for CPET [12] and most frequently recommended [9,11,13]. The influence of a possible training effect on the results was minimized by performing tests in random order.
Heart failure severity was assessed according to peak O2 in the 10-min test, using the Weber classification [1]. CPET parameters varied according to HF severity, as expected. For the 10-min test, peak exercise heart rate, O2 pulse and work-rate achieved were lower, the more severe the HF. Also, peak exercise ventilation and tidal volume were lowest in patients with the greatest HF severity [16]. Patients with the greatest severity of HF also showed a higher inappropriate ventilation as documented by a steeper E/CO2 slope and a higher E/CO2 at anaerobic threshold; as a consequence, peak exercise PetO2 was higher and PetCO2 was lower in the more severe HF patients (Table 2).
Peak O2 was significantly lower in the 5-min as compared to the 10- and 15-min tests. This may relate to the large work-rate increase in a short time period dictated by the 5-min protocol.
This imposes a heavy load early in exercise, forcing the patient to stop exercising early because of limited O2 transport. The inability to regenerate adenosine triphosphate (ATP), aerobically, may account for the failure to sustain muscle contraction and cause early muscle fatigue. Indeed, the more shallow O2/work-rate for the more rapid rates of increase in work-rate (Table 1), undoubtedly relates to the failure of the cardiac output to increase at the rate required to provide the muscles with the O2 needed to regenerate ATP aerobically. The O2/work-rate slope is frequently utilized to assess the adequacy of O2 flow and utilization in the periphery [15]. The exercise protocol affected the O2/work-slope with its value being lower with greater work increments (Fig. 2). This was a trend in all classes of HF and similar to changes in normal subjects, as described by Hansen et al. [15]. Albeit we have not partitioned the O2/work-rate relationship between above and below anaerobic threshold, the reason for the observed differences might be due to the zone of work above the anaerobic threshold being O2-flow-dependent, as described by Wasserman et al. [17] and thereby be subject to a decreasing O2/work-rate slope when the O2 demand is faster than the circulation can transport O2. As shown in Fig. 1, O2/work-rate is lowest for the most severely impaired patients in all the exercise protocols. The more shallow O2/work-rate for the fast ramp may bias the grading of HF severity and the decision of cardiac transplantation, if work-rate is used to grade the patient's impairment [18,19].
While the exercise protocol influenced peak exercise ventilation, it did not affect the E/CO2 slope, which is an index of coupling of ventilation and lung perfusion. As previously described, the slope was higher as HF severity worsened [10,20,21]. The E/CO2 relationship is calculated during exercise, in the range of work below the ventilatory compensation point for the exercise-induced lactic acidosis, thus avoiding the non-linearity to ventilation caused by lactic acidosis. The E/CO2 slope is a relevant indicator of HF survival, independent of peak exercise O2 [10,22] as it is O2 at anaerobic threshold [19]. The absence of a change in E/CO2 slope and O2 at anaerobic threshold with increasing rates of work-rate demonstrates the robust nature of both these measurements and their physiological significance. Indeed, our findings reinforce the observation of Gitt et al. [23] who suggests the combined use of E/CO2 slope and O2 at anaerobic threshold for precise HF prognosis. Only the work-load at which anaerobic threshold was identified was influenced by the protocol. This is as expected because of the time lag between the change in work-rate and metabolic events in the muscle.
In conclusion, we showed that, when evaluating HF patients, the exercise protocol influences the peak imposed cycle ergometer work-load and, to a small degree, the O2/work-rate. Peak O2 is slightly reduced, only for the most rapid ramp protocol. E/CO2 slope and O2 at anaerobic threshold are unaffected.
|
Acknowledgments |
|---|
|
TopAbstract1. Methods2. Results3. DiscussionAcknowledgmentsReferences |
|---|
The authors are indebted to Maria Luisa Scapin, RN for excellent technical assistance.
|
References |
|---|
|
TopAbstract1. Methods2. Results3. DiscussionAcknowledgmentsReferences |
|---|
- Weber K.T., Janicki J.S. Cardiopulmonary exercise testing for evaluation of chronic heart failure. Am. J. Cardiol. (1985) 55:22A–31A.[CrossRef][Medline]
- Meyers J., Gullestad L. The role of exercise and gas-exchange measurement in the prognostic assessement of patient with heart failure. Curr. Opin. Cardiol. (1998) 13:145–155.[Web of Science][Medline]
- Cohn J., Johnson G.R., Shabetai R., Loeb H., Tristani F., Rector T., et al. Ejection fraction, peak oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepepinephrine as determinants of prognosis in heart failure. Circulation (1993) 87:V15–V16.
- Stelken A.M., Younis L.T., Jennison S.H., Miller D.D., Miller L.W., Shaw L.J., et al. Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy. J. Am. Coll. Cardiol. (1996) 27:345–352.[Abstract]
- Chua T., Ponikowski P., Harrington D., Anker S.D., Webb-Peploe K., Clark A.L., et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J. Am. Coll. Cardiol. (1997) 29:1585–1590.[Abstract]
- Stevenson L.W., Steimle A.E., Fonarow G., Kermani M., Kermani D., Hamilton M.A., et al. Improvement in exercise capacity of candidates awaiting heart transplantation. J. Am. Coll. Cardiol. (1995) 25:163–170.[Abstract]
- Guazzi M., Palermo P., Pontone G., Susini F., Agostoni P. Synergistic efficacy of enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure. Am. J. Cardiol. (1999) 84:1038–1043.[CrossRef][Web of Science][Medline]
- Agostoni P.G., Marenzi G.C., Pepi M., Doria E., Salvioni A., Perego G.B., et al. Isolated ultrafiltration for moderate heart failure. J. Am. Coll. Cardiol. (1993) 21:424–431.[Abstract]
- Working Group on Cardiac Rehabilitation and Exercise Physiology and Working Group on Heart Failure of the European Society of Cardiology: recommendation for exercise testing in chronic heart failure patients. Eur. Heart J. (2001) 22:37–45.
[Free Full Text] - Kleber F.X., Vietzke G., Wernecke K.D., Bauer U., Opitz C., Wensel R., et al. Impairment of ventilatory efficacy in heart failure. Prognostic impact. Circulation (2000) 101:2803–2809.
[Abstract/Free Full Text] - Myers J., Froelicher V.F. Optimizing the exercise test for pharmacological investigation. Circulation (1990) 82:1839–1846.
[Abstract/Free Full Text] - Buchfuhrer M., Hansen J.E., Robinson T.E., Sue D.Y., Wasserman K., Whipp B.J. Optimizing the exercise protocol for cardiopulmonary assessment. J. Appl. Physiol. (1983) 55:1558–1564.
[Abstract/Free Full Text] - Fletcher G.F., Balady G., Froelicher V.F., Hartley L.H., Haskell W.L., Pollock M.L. Exercise standards a statement for healthcare professionals from the American Heart Association. Circulation (1995) 91:580–615.
[Free Full Text] - Elborn J.S., Stanford C.F., Nicholls D.P. Reproducibility of cardiopulmonary parameters during exercise in patients with chronic heart failure. The need for a preliminary test. Eur. Heart J. (1990) 11:75–81.
[Abstract/Free Full Text] - Hansen J.E., Sue D.Y., Oren A., Wasserman K. Relation of oxygen uptake to work rate in normal men and men with circulatory disorders. Am. J. Cardiol. (1987) 59:669–674.[CrossRef][Web of Science][Medline]
- Wasserman K., Zhang Y.Y., Gitt A., Belardinelli R., Koike A., Lubarsky L., et al. Lung function and exercise gas exchange in chronic heart failure. Circulation (1997) 96:2221–2227.
[Abstract/Free Full Text] - Wasserman K., Stringer W., Xin-Guo S., Koike A. Circulatory coupling of external to muscle respiration during exercise. In: Cardiopulmonary exercise testing and cardiovascular health—Wasserman K., ed. (2002) Armonk (NY): Futura publishing. 3–25.
- Mancini D., Eisen H., Kussmaul W., Mull R., Edmunds H.L., Wilson J.R. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation (1991) 83:778–786.
[Abstract/Free Full Text] - Meyers J., Gullestad L., Vagelos R., Do D., Bellin D., Ross H., et al. Clinical, hemodynamic and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann. Intern. Med. (1998) 129:286–293.
[Abstract/Free Full Text] - Clark A.L., Poole-Wilson P.A., Coats A.J.S. Relation between ventilation and carbon dioxide production in patients with chronic heart failure. J. Am. Coll. Cardiol. (1992) 20:1326–1332.[Abstract]
- Chua T.P., Ponikowski P., Harrington D., Anker S., Webb-Peploe K., Clark A., et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J. Am. Coll. Cardiol. (1997) 29:1585–1590.[Abstract]
- Francis P.D., Shamin W., Ceri Davies L., Piepoli M.F., Ponikoski P., Anker S.D., et al. Cardiopulmonary exercise testing for prognosis in chronic heart failure. Eur. Heart J. (2000) 21:154–161.
[Abstract/Free Full Text] - Gitt A.K., Wasserman K., Kilkowski C., Kleeman T., Kilkowski A., Bangert M., et al. Exercise anaerobic threshold and ventilatory efficiency identify heart failure patients for high risk of early death. Circulation (2002) 106:3079–3084.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Agostoni, M. Emdin, U. Corra, F. Veglia, D. Magri, C. C. Tedesco, E. Berton, C. Passino, E. Bertella, F. Re, et al. Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients Eur. Heart J., October 1, 2008; 29(19): 2367 - 2372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Agostoni, M. Contini, G. Cattadori, A. Apostolo, S. Sciomer, M. Bussotti, P. Palermo, and C. Fiorentini Lung function with carvedilol and bisoprolol in chronic heart failure: Is {beta} selectivity relevant? Eur J Heart Fail, August 1, 2007; 9(8): 827 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mancini and T. H. LeJemtel Is Ventilatory Classification Preferable to Peak Oxygen Consumption for Risk Stratification in Heart Failure? Circulation, May 8, 2007; 115(18): 2376 - 2378. [Full Text] [PDF]
|
|
|
|
|
|
P. Agostoni, M. Contini, A. Magini, A. Apostolo, G. Cattadori, M. Bussotti, F. Veglia, D. Andreini, and P. Palermo Carvedilol reduces exercise-induced hyperventilation: A benefit in normoxia and a problem with hypoxia Eur J Heart Fail, November 1, 2006; 8(7): 729 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Agostoni Cardiopulmonary exercise testing for heart failure patients: a hodgepodge of techniques, parameters and interpretations. In other words, the need for a time-break Eur. Heart J., March 2, 2006; 27(6): 633 - 634. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||